tbuckley/cabot-search huggingface dataset:
Abstract 920: Real-world biomarker testing patterns in metastatic castration-resistant prostate cancer patients
Authors: Simon Blanc, Gboyega Adeboyeje, Liam Lee, Mike Gart, William Saunders, Brandon Wang, Poras Dave, Sandy English, Prateesh Varughese, Arthur Sillah
Journal: Cancer Research (2023)

Abstract Introduction: Homologous recombination repair mutations (HRRm) result in an accumulation of genetic aberrations and genomic instability. HRRm are estimated to be present in up to 28% of patients (pts) with advanced prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Testing for HRRm may inform treatment choice in pts with mCRPC. The aim of the study was to assess HRRm testing rate and describe pts factors associated with testing in treated mCRPC pts. Methods: We identified pts with mCRPC on treatment from 5/1, 2020 through 3/31, 2022 from the Integra Connect PrecisionQ de-identified database, an electronic medical record (EMR) and claims database of US cancer pts in community oncology. We defined HRRm testing as the receipt of any test for alterations in 1 or more of the following genes: BRCA 1/2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54. We described age and race at diagnosis (dx), cancer stage and Gleason score at staging, and line of therapy (LOT), Eastern Cooperative Oncology Group (ECOG) performance status, metastatic sites and prostate-specific antigen (PSA) values at date closest to mCRPC diagnosis. Categorical data were reported as counts and percentages, and continuous data were summarized as medians (IQR). Results: The study cohort comprised 798 pts (HRRm tested, n=389, 48.7%). Most pts were white (81.7%), with a median (IQR) age of 68 (54-82) years at dx. Most pts had high-grade mCRPC, with Gleason scores of 7-8 (43.3%) or 9-10 (47.9%). The majority of pts were stage IV (74.0%), and on their first LOT (44.6%) at mCRPC diagnosis. A higher proportion of pts ≥80 years were not HRRm-tested (61.5%) vs. pts ≤59 (46.6%). Compared to white pts, a higher proportion of black/African American pts were HRRm non-tested (48.6% vs 41.5%). Tested pts had better ECOG status compared to non-tested pts (0 - 1: 91.0% vs 86.8%). 77.1% of tested pts had a bone metastasis compared to 73.4% of non-tested. A higher proportion of tested pts were diagnosed with mCRPC in a later LOT than those not tested. Conclusion: We found a testing rate for HRRm of 49% in US mCRPC pts receiving routine care. There were modest unadjusted differences in demographic and clinical features between tested and non-tested pts. There is a need for further research to examine the value of HRRm testing in mCRPC pts. Citation Format: Simon Blanc, Gboyega Adeboyeje, Liam Lee, Mike Gart, William Saunders, Brandon Wang, Poras Dave, Sandy English, Prateesh Varughese, Arthur Sillah. Real-world biomarker testing patterns in metastatic castration-resistant prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 920.
Abstract 1415: The search for molecular biomarkers of relapse in early stage lung adenocarcinoma
Authors: Honggang Ke, Zhongying Jing
Journal: Cancer Research (2023)

Abstract Background: Recurrence cannot be completely prevented by resection or chemotherapy. Molecular biomarkers reported in previous studies have the potential to predict the recurrence risk of lung adenocarcinoma (LUAD), but the results were controversial. Methods: We retrospectively analyzed the molecular characteristics of the 218 early-stage patients with lung adenocarcinoma based on 599 gene-panel target sequencing. All the patients received no neoadjuvant therapy and no EGFR-TKI treatment. The follow-up information on recurrence was complete. Univariate and multivariate analyses were performed using the Cox proportional hazard models to investigate whether the common alterations in EGFR and KRAS were prognostic factors for relapse-free survival(RFS). Results: Among all the enrolled patients, the mutation rates of EGFR and KRAS were 47.6% and 9.3%, respectively. EGFR mutation was not proved to be a prognostics signature of relapse for lung adenocarcinoma regardless univariate and multivariate analysis (univariate: HR, 1.11; 95%CI, 0.82-1.50, P = 0.49; multivariate: HR, 1.18; 95%CI, 0.86-1.64, P = 0.31). The univariate and multivariate analysis identified KRAS alteration as an independent prognostic factor for a shorter RFS (univariate: HR, 1.64; 95%CI, 0.75-2.43, P &amp;lt; 0.05; multivariate: HR, 1.66; 95%CI, 1.19-2.32, P &amp;lt;0.05). For patients in pathological stage I, the patients with KRAS alterations showed significant recurrent risk compared with wild-type patients (HR, 2.02; 95%CI, 1.38-2.96; P &amp;lt;0.0.01). Conclusion: KRAS alterations rather than EGFR alterations were prognostic biomarkers of relapse for early-stage lung adenocarcinoma, especially for patients in pathological stage I. Citation Format: Honggang Ke, Zhongying Jing. The search for molecular biomarkers of relapse in early stage lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1415.
Abstract 1977: Body mass index genetic risk score and obesity related cancer risk in Black and White adults
Authors: Peter T. Katzmarzyk, Shengping Yang, Justin C. Brown, Emily F. Mire, Jovanny Zabaleta
Journal: Cancer Research (2023)

Abstract A total of 13 cancers are known to be strongly associated with obesity. The purpose of this study was to examine the association between a composite genotype risk score (GRS) for high body mass index (BMI) and the odds of obesity-related cancer. A nested case-control study was created within the Pennington Center Longitudinal Study, an ongoing prospective cohort study of the effects of obesity and lifestyle factors on the development of chronic diseases and premature mortality in Black and White Americans. A total of 459 participants developed an obesity-related cancer, and after stratification by sex and race, incidence density sampling was applied to select matched control participants (2:1) of the same age as cases (± 2 y). After deletion of participants with missing data, the analytic sample included 1242 participants (435 cases;136 Black, 299 White). A BMI GRS was derived using 21 single nucleotide polymorphisms (SNPs) with consistent evidence of association from the literature and which showed concordant associations in effect size and direction in our cohort. The GRS score was computed by summing the number of BMI risk alleles. In a model including age, race, sex, exam year and smoking as covariates, the BMI GRS was significantly associated with obesity-related cancer [odds ratio (OR): 1.18; 95% confidence interval: 1.04, 1.34; p=0.01]. Further adjustment for BMI did not change the association [1.20; 1,06-1.36; p=0.004]. In conclusion, the BMI GRS appears to provide added value in identifying obesity-related cancer risk, even after adjustment for BMI. Future studies are required to validate these results and better delineate the phenotypic and genetic contributions of BMI to obesity-related cancer risk. Citation Format: Peter T. Katzmarzyk, Shengping Yang, Justin C. Brown, Emily F. Mire, Jovanny Zabaleta. Body mass index genetic risk score and obesity related cancer risk in Black and White adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1977.
Abstract 1414: The role of chromosome arm 3p and human papillomavirus on proliferation, differentiation, and metastasis in squamous cancers
Authors: Samyukta Mallick, Alison M. Taylor
Journal: Cancer Research (2023)

Abstract Squamous Cell Carcinoma (SCC) is an aggressive form of cancer that develops in the mucosal epithelium of the digestive and respiratory tracts as well as on the skin. Two major risk factors for development of SCC are carcinogen exposures, such as alcohol and tobacco, and Human Papillomavirus (HPV) infection. Viral- and carcinogen-driven SCCs have differential responses to radiation, chemotherapy, and immunotherapy, with HPV+ SCCs responding better to these treatments than HPV- carcinomas. Analysis of aneuploidy patterns of genomic samples from The Cancer Genome Atlas (TCGA) have shown that squamous cancers cluster together and are characterized by gain of chromosome arm 3q gain and loss of chromosome arm 3p. However, while HPV+ SCCs show similar rates of 3q gain, they have significantly lower rates of 3p loss, suggesting that 3p deletion and HPV infection might have overlapping roles in cancer initiation and/or progression. In addition, the degree to which these two paths of tumor development contribute to differences in disease progression and outcome has been largely unexplored. We have identified a strong correlation between 3p deletion and high epithelial-mesenchymal transition (EMT) gene signature across all cancer types. Interestingly, interferon signaling has been found to be upregulated in non-squamous cancers upon 3p deletion but downregulated in squamous cancers with 3p deletion. SCCs positive for HPV infection show decreased expression of EMT genes and increased expression of genes in interferon signaling and cell cycle checkpoint pathways. Together, the results of these TCGA analyses suggest mechanisms by which chromosome 3p deletion and HPV infection may affect cancer progression and are currently being validated in vitro in a panel of squamous cancer cell lines. Additionally, we will use a targeted CRISPR-Cas9 system developed in our lab to delete chromosome 3p, as well as transfect HPV oncoproteins, in normal keratinocytes to create isogenic models. With these models, we will study the role of individual aneuploidy events in tumorigenesis, tumor development, and metastasis in the context of HPV positive and negative SCC. Citation Format: Samyukta Mallick, Alison M. Taylor. The role of chromosome arm 3p and human papillomavirus on proliferation, differentiation, and metastasis in squamous cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1414.
Abstract 855: Model-informed drug design (MIDD) exploration of a theoretical CD47xTAA bispecific antibody using available data from magrolimab, an anti-CD47 monoclonal antibody
Authors: Emily A. Pace, Bjorn L. Millard
Journal: Cancer Research (2023)

Abstract Purpose: The goal of this study is to outline the process and utility of using fit-for-purpose, semi-mechanistic PK/PD modeling to inform the design of a theoretical CD47 bispecific antibody targeted to a generic tumor-associated antigen (CD47xTAA bsAb) with improved efficacy, tolerability, and PK compared to single target anti-CD47 therapies. Approach: To help guide the CD47xTAA bsAb design, a 3-compartment human model was built to include a target-mediated drug disposition (TMDD) component from CD47 expressed on red blood cells (RBC), white blood cells (WBC), and cells in the peripheral compartment. The model was parameterized using available literature data and calibrated against magrolimab human PK data that exhibited potential TMDD. The magrolimab model was used to identify key CD47 receptor occupancy (RO) thresholds associated with tolerability (the priming dose threshold) and efficacy (the recommended Phase 2 dose/RP2D threshold). Next, assumed drug properties and TAA expression levels for a CD47xTAA bsAb were implemented in a similar human model and drug PK and doses required to match key CD47 RO thresholds were explored across a range of single-arm binding affinities. Results: The calibrated magrolimab model projected target engagement levels on RBCs and WBCs and showed rapid antibody-induced CD47 pruning on RBCs that is consistent with clinical PD measurements. At TAA binding affinities that produce sufficient binding to tumor antigen, the model predicts that lowering the CD47 binding affinity allows for a higher starting dose that matches the priming threshold, while lowering the dose required to match the RP2D threshold. The model also shows that lowering the binding affinity to CD47 may improve PK exposure in the tumor compartment by reducing systemic CD47 TMDD. Conclusions: This modeling exercise demonstrates how semi-mechanistic PK/PD models can be used in model-informed drug design (MIDD) by leveraging the targeting advantage of avid bispecific antibody therapies and by using publicly available preclinical and clinical data. Furthermore, these model projections can help inform future studies with bispecific CD47 drug candidates. Citation Format: Emily A. Pace, Bjorn L. Millard. Model-informed drug design (MIDD) exploration of a theoretical CD47xTAA bispecific antibody using available data from magrolimab, an anti-CD47 monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 855.
Abstract 1166: APOBEC deaminases compete with tobacco smoking mutagenesis and affect age at onset of lung cancer
Authors: Tongwu Zhang, Jian Sang, Phuc H. Hoang, Wei Zhao, Jennifer Rosenbaum, Leszek J. Klimczak, John McElderry, Alyssa Klein, Christopher Wirth, Erik N. Bergstrom, Marcos Díaz-Gay, Raviteja Vangara, Amy Hutchinson, Scott M. Lawrence, Nathan Cole, Bin Zhu, Teresa M. Przytycka, Jianxin Shi, Neil E. Caporaso, Robert Homer, Angela C. Pesatori, Dario Consonni, Stephen J. Chanock, David C. Wedge, Dmitry A. Gordenin, Ludmil B. Alexandrov, Reuben S. Harris, Maria Teresa Landi
Journal: Cancer Research (2023)

Abstract APOBEC enzymes are part of the innate immunity and are responsible for restricting viruses and retroelements by deaminating cytosine residues. Most solid tumors harbor different levels of somatic mutations attributed to the off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B). However, how APOBEC3A/B interact with exogenous mutagenic processes in shaping tumor development is largely unknown. Here, by combining deep whole-genome sequencing with multi-omics profiling of 309 lung cancers from smokers with detailed tobacco smoking information, we identify two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations, whereas HAS for A3A-like mutagenesis and TP53 mutations. Unlike APOBEC3A, APOBEC3B expression is strongly associated with an upregulation of the base excision repair pathway. Hypermutation by unrepaired A3A and tobacco smoking mutagenesis combined with TP53-induced genomic instability can trigger senescence, apoptosis, and cell regeneration, as indicated by telomere shortening, high expression of pulmonary healing signaling pathway and stemness markers in HAS. The expected association of tobacco smoking exposure with genomic/epigenomic changes are not observed in HAS, a plausible consequence of frequent cell senescence or apoptosis. HAS tumors have slower clonal expansion and older age at onset compared to LAS, particularly in heavy smokers, consistent with high proportions of newly generated, unmutated cells in HAS. These findings show how heterogeneity in mutational burden across competing mutational processes and cell types contributes to tumor development, with important clinical implications. Citation Format: Tongwu Zhang, Jian Sang, Phuc H. Hoang, Wei Zhao, Jennifer Rosenbaum, Leszek J. Klimczak, John McElderry, Alyssa Klein, Christopher Wirth, Erik N. Bergstrom, Marcos Díaz-Gay, Raviteja Vangara, Amy Hutchinson, Scott M. Lawrence, Nathan Cole, Bin Zhu, Teresa M. Przytycka, Jianxin Shi, Neil E. Caporaso, Robert Homer, Angela C. Pesatori, Dario Consonni, Stephen J. Chanock, David C. Wedge, Dmitry A. Gordenin, Ludmil B. Alexandrov, Reuben S. Harris, Maria Teresa Landi. APOBEC deaminases compete with tobacco smoking mutagenesis and affect age at onset of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1166.
Abstract 1348: Neutrophil pro-tumorigenic role in progression and therapy resistance in pancreatic ductal adenocarcinoma
Authors: Reegan Sturgeon, Paran Goel, Caitlin Molczyk, Surindar K. Batra, Rakesh Singh
Journal: Cancer Research (2023)

Abstract Pancreatic cancer (PC) continues to be a challenge for today’s therapeutics, with a meager 5-year survival rate of 11%. Due to the pancreas’ location, patients often receive diagnosis late, leaving them with limited treatment options. Often, they fail to respond to chemotherapy regimens or develop resistance to those therapies. Tumor-promoting inflammation is a hallmark of cancer that contributes to tumor cells’ survival and proliferation. Infiltrating leukocytes and pro-inflammatory cytokines released into the tumor microenvironment (TME) often cause this inflammation. Previously we have determined that inflammation and CXCR2 ligand expression increases with pancreatic ductal adenocarcinoma (PDAC) progression. In the present study, we examined the role of neutrophil recruitment in PDAC progression using Kras-dependent KC and KPC murine models. Our data suggest a positive association between tumor-associated neutrophils (TANs) and PDAC progression. Furthermore, the frequency of neutrophil extracellular traps (NETs) also increased as the disease progressed. In vitro, we observed PDAC cell condition-media enhanced survival of neutrophils in a concentration-dependent manner. Moreover, increased survival was associated with disease aggressiveness and therapy resistance. Additionally, we observed that PDAC-conditioned media modulated the expression of immunoregulatory cytokines and chemokines in neutrophils. Together, our data suggest that increased recruitment of TANs supports PDAC progression, and PDAC cell-neutrophil interaction modulates neutrophil survival and immunoregulatory phenotype. Citation Format: Reegan Sturgeon, Paran Goel, Caitlin Molczyk, Surindar K. Batra, Rakesh Singh. Neutrophil pro-tumorigenic role in progression and therapy resistance in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1348.
Abstract 2268: Single cell RNA sequencing defines dynamic immune cell subsets in serial colon and peripheral blood samples in a patient with checkpoint inhibitor-induced colitis
Authors: Jacqueline E. Mann, Liliana Lucca, Matthew Austin, Ross D. Merkin, Lilach Aizenbud, Kevan Herold, Marie Robert, Harriet M. Kluger
Journal: Cancer Research (2023)

Abstract Background: Immune checkpoint inhibition is an increasingly popular strategy for the management of numerous malignancies. Unfortunately, severe inflammatory toxicities affect up to 60% of patients, often leading to treatment discontinuation in settings where few alternative therapies are available to control disease. Checkpoint inhibitor induced colitis is a common toxicity for which the underlying mechanisms are poorly defined. Methods: To better understand the changing colon-specific and peripheral immune environments over the course of disease progression and treatment, we collected blood and colon tissue from a Merkel Cell carcinoma patient who developed colitis after treatment with pembrolizumab. We performed 10X Genomics single cell RNA sequencing on samples collected before, during and after checkpoint inhibition and various interventions to mitigate toxicity. Results: We identified both shared and colon-exclusive clonal expansion of T cells defined by distinct transcriptional programs, including cytotoxicity, memory, and proliferation markers, at various stages of the disease process. These clones decreased dramatically in the colon after infliximab and vedolizumab therapies. Conclusions: We identified several distinct T cell subsets as potential drivers of colitis in the colon. T cell clones that potentially recognize colonic tissue with a high degree of specificity can be harnessed for therapeutic intervention. Our findings emphasize the need for a more detailed understanding of the immune environment in the colon and suggest the potential for peripheral blood as a readout for immune activity during CPI treatment. Citation Format: Jacqueline E. Mann, Liliana Lucca, Matthew Austin, Ross D. Merkin, Lilach Aizenbud, Kevan Herold, Marie Robert, Harriet M. Kluger. Single cell RNA sequencing defines dynamic immune cell subsets in serial colon and peripheral blood samples in a patient with checkpoint inhibitor-induced colitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2268.
Abstract 82: Role of MSC-derived CXCL1 in bone-metastatic prostate cancer
Authors: Catherine S. Johnson, Diane Costanzo-Garvey, Massar Alsamraae, Jeremy S. Frieling, Leah M. Cook
Journal: Cancer Research (2023)

Abstract In 2022, the American Cancer Society estimates that over 34,000 men will die of PCa, largely due to metastatic PCa. Up to 90% of advanced prostate cancers metastasize to bone, and there are currently no curative therapies for bone metastatic prostate cancer (BM-PCa). BM-PCa cells interact with bone-forming osteoblasts and bone-resorbing osteoclasts to induce aberrant bone remodeling, which leads to skeletal related adverse events such as increased risk of fractures, bone pain, and poor quality of life. Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into osteoblasts. Cook lab data show BM-PCa cells interact with MSCs and promote MSC differentiation into osteoblasts. Microarray analysis of MSC gene expression changes in response to BM-PCa show significant upregulation of CXCL8. To determine the importance of MSC-derived CXCL8 to BM-PCa, CXCL1 (the murine homolog of CXCL8) was genetically deleted in murine MSCs. While CXCL1 knock out (KO) had no significant impact on MSC proliferation, loss of CXCL1 decreased MSC migration, which suggests upregulation of MSC CXCL1 by BM-PCa cells functions to increase MSC migration into the tumor microenvironment. Additionally, CXCL1 KO MSCs have altered osteoblastic differentiation, whereas adipogenic differentiation was unchanged. RNA sequencing of MSCs stably expressing CXCL1-targeted shRNAs compared to scrambled controls show extensive gene expression changes, including altered expression of multiple osteogenic genes. In vivo data show intratibial co-injection of CXCL1 KO MSCs with murine RM1 BM-PCa cells in an immunocompetent mouse model increases tumor burden compared with co-injection of wildtype MSCs and BM-PCa cells, indicating a role for MSC-derived CXCL1 in suppressing BM-PCa tumor growth in bone. This project shows for the first time the importance of CXCL1 in MSC migration, osteogenesis, gene expression, suppression of BM-PCa progression in bone and tumor-induced bone remodeling. Citation Format: Catherine S. Johnson, Diane Costanzo-Garvey, Massar Alsamraae, Jeremy S. Frieling, Leah M. Cook. Role of MSC-derived CXCL1 in bone-metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 82.